4-Methylmorpholine → (R)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-carbamoyl-ethoxy)-2-fluoro-benzyl]-nicotinamide

HRID 351007Notes

Reaction equation

HRID 351007 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N:35]1CCOCC1.ClC(OCC(C)C)=O.CO.ClCCl>COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:35])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 9955578CP-671305HCID 21226129Dichloromethane methanol

Product 1

HCID 10275871(R)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-carbamoyl-ethoxy)-2-fluoro-benzyl]-nicotinamideYield 60.1%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
-10 °C

Procedure

To a stirred solution of (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid (0.25 g, 0.55 mmol) in ethylene glycol dimethyl ether (20 mL) at −10° C. was added N-methyl morpholine (0.06 mL, 0.55 mmol) followed by dropwise addition of isobutyl chloroformate (0.071 mL, 0.55 mmol). The turbid solution was stirred at −10° C. 10 min. Ammonia gas was bubbled through the reaction mixture 10 min, which was then warmed to room temperature and stirred a further 15 min. The reaction mixture was partitioned between chloroform and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a white solid. Flash column chromatography (1% methanol/dichloromethane) yielded 0.15 g of a white solid (60% yield).

Workup

  1. custom10 min
  2. customAmmonia gas was bubbled through the reaction mixture 10 min, which
  3. temperaturewas then warmed to room temperature
  4. stirringstirred a further 15 min
  5. customThe reaction mixture was partitioned between chloroform and water
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customto afford a white solid

Sources & evidence

ORD record
ord-871a02cb36e54c8f81a2d3bc5fe00e3c
Source dataset
uspto-grants-2007_02
Patent number
US07183293B2

Reaction notes

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